Recent studies in our laboratory revealed that a partial deficiency of glutamate dehydrogenase (GDH) and abnormal glutamate metabolism are specific biochemical defects of a form of recessively-inherited olivopontocerebellar atrophy (OPCA). Additional studies revealed evidence for the cellular presence of two distinct forms of GDH in human leukocytes and fibroblasts as well as in rat brain. One isoenzyme, which is "soluble", is heat resistant (at 47.5 C) where as the other isoenzyme, which is "particulate", is heat-labile (at 47.5 C). Determination of both GDH isoenzymes in leukocytes from patients with recessive OPCA revealed complete deficiency of the heatlabile GDH. These results strongly suggest that deficiency of the heat-sensitive GDH is the actual gene defect of this form of recessive OPCA. We propose: (1) To extend the current investigations on the activity of the two GDH isoenzymes in leukocytes from patients with OPCA as well as patients with other degenerative neurological disorders to further consolidate our data on the phenotype associated with GDH deficiency. (2) To investigate whether a deficiency of the heat-sensitive GDH is also present in cultured skin fibroblasts from these patients. (3) To evaluate the activities of the two GDH isoenzymes in leukocytes and cultured skin fibroblasts from obligated heterozygotes (parents and children of GDH-deficient patients). (4) To purify the rat and human brain and liver GDH isoenzymes and to compare their properties. (5) To further characterize the GDH isoenzymes in leukocytes and fibroblasts from patients and controls and to develop improved methods for their separation. (6) To expand the current studies on systemic metabolism of glutamate in patients with GDH deficiency as well as patients with other degenerative neurological disorders. (7) To further explore the possible role of GDH-activating agents such as the branched-chain amino acids in arresting or reversing the course of the GDH-deficient neurological disorders.